Antidepressant azaheterocyclylmethyl derivatives of heterocycle-fused benzodioxans

ABSTRACT

Compounds of the Formula: 
                         
are useful for the treatment of depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as premenstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction and related illnesses.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 10/659,167filed Sep. 10, 2003, now U.S. Pat. No. 7,135,479, which claims thebenefit of U.S. application Ser. No. 60/410,168, filed Sep. 12, 2002,the disclosure of which are incorporated herein by reference in theirentireties.

FIELD OF THE INVENTION

This invention relates to antidepressant azaheterocyclylmethylderivatives of heterocycle-fused benzodioxans, to processes forpreparing them, methods of using them and to pharmaceutical compositionscontaining them.

BACKGROUND OF THE INVENTION

Major depression is a serious health problem affecting more than 5% ofthe population, with a lifetime prevalence of 15-20%.

Selective serotonin reuptake inhibitors have produced success intreating depression and related illnesses and have become among the mostprescribed drugs. They nonetheless have a slow onset of action, oftentaking several weeks to produce their full therapeutic effect.Furthermore, they are effective in less than two-thirds of patients.

Serotonin selective reuptake inhibitors (SSRIs) are well known for thetreatment of depression and other conditions. SSRIs work by blocking theneuronal reuptake of serotonin, thereby increasing the concentration ofserotonin in the synaptic space, and thus increasing the activation ofpostsynaptic serotonin receptors.

However, although a single dose of an SSRI can inhibit the neuronalserotonin transporter which would be expected to increase synapticserotonin, long-term treatment is required before clinical improvementis achieved.

It has been suggested that the SSRIs increase the serotonin levels inthe vicinity of the serotonergic cell bodies and that the excessserotonin activates somatodendritic autoreceptors, 5HT_(1A) receptors,causing a decrease in serotonin release in major forebrain areas. Thisnegative feedback limits the increment of synaptic serotonin that can beinduced by antidepressants.

A 5HT_(1A) antagonist would limit the negative feedback and shouldimprove the efficacy of the serotonin reuptake mechanism (Perez, V., etal., The Lancet, 349:1594-1597 (1997)). Such a combination therapy wouldbe expected to speed up the effect of the serotonin reuptake inhibitor.

Thus, it is highly desirable to provide improved compounds which bothinhibit serotonin reuptake and which are antagonists of the 5HT_(1A)receptor.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a group of novelcompounds of Formula I:

wherein

-   -   Q is

-   -   R¹, R² and R³ are, independently, hydrogen, hydroxy, halo,        cyano, carboxamido, carboalkoxy of two to six carbon atoms,        trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6        carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2        to 6 carbon atoms, amino, mono- or di-alkylamino in which each        alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon        atoms, alkanesulfonyl of 1 to 6 carbon atoms or        alkanesulfonamido of 1 to 6 carbon atoms;    -   X and Y are, independently, hydrogen, hydroxy, halo, cyano,        carboxamido, carboalkoxy of two to six carbon atoms,        trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6        carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2        to 6 carbon atoms, amino, mono- or di-alkylamino in which each        alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon        atoms, alkanesulfonyl of 1 to 6 carbon atoms or        alkanesulfonamido of 1 to 6 carbon atoms, or X and Y, taken        together, form —N═C(R⁴)—C(R⁵)═N—, —N═C(R⁴)—C(R⁶)═CH—,        —N═C(R⁴)—N═CH—, —N═C(R⁴)—O—, —NH—C(R⁷)═N— or —NH—C(R⁸)═CH—;    -   R⁴ and R⁵ are, independently, hydrogen, halo, amino, mono- or        di-alkylamino in which each alkyl group has 1 to 6 carbon atoms        or alkyl of 1 to 6 carbon atoms;    -   R⁶ is hydrogen or alkyl of 1 to 6 carbon atoms;    -   R⁷ is hydrogen, halo, trifluoromethyl, pentafluoroethyl, amino,        mono- or di-alkylamino in which each alkyl group has 1 to 6        carbon atoms or alkyl of 1 to 6 carbon atoms;    -   R⁸ is hydrogen, halo, trifluoromethyl, pentafluoroethyl, or        alkyl of 1 to 6 carbon atoms;    -   Z is O, S, or NR⁹, in which R⁹ is hydrogen or alkyl of 1 to 6        carbon atoms;    -   n is an integer 0, 1, or 2;    -   m is an integer from 1 to 4, provided that m+n≦4 and that when        m=n=2, and Q is b then X and Y are not NH—C(R⁸)═CH—; and    -   p is an integer from 1 to 3, provided that p+n is 2 or 3;    -   or a pharmaceutically acceptable salt thereof.

R¹ is preferably hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6carbon atoms or alkoxy of 1 to 6 carbon atoms. More preferably, R¹ ishydrogen, halo or alkoxy of 1 to 6 carbon atoms. In still more preferredembodiments of the present invention, R¹ is hydrogen.

R² and R³ are preferably independently selected from hydrogen, hydroxy,halo, cyano, carboxamido, alkyl of 1 to 6 carbon atoms, or alkoxy of 1to 6 carbon atoms. In still more preferred embodiments of the presentinvention R² and R³ are preferably independently selected from hydrogen,cyano or halogen.

R⁴ and R⁵ are preferably independently hydrogen, amino or alkyl of 1 to6 carbon atoms. More preferably, R⁴ and R⁵ are independently hydrogen oralkyl of 1 to 3 carbon atoms.

R⁷ and R⁸ are preferably independently selected from hydrogen,trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms. Morepreferably, R⁷ and R⁸ are independently hydrogen, trifluoromethyl oralkyl of 1 to 3 carbon atoms.

R⁶ is preferably hydrogen or alkyl of 1 to 3 carbon atoms, Z ispreferably NR⁹ in which R⁹ is hydrogen or alkyl of 1 to 3 carbon atoms,n is preferably 0 or 1, m is preferably 1 to 3 and p is preferably 1 or2.

In other preferred embodiments of the invention are provided compoundsof Formula Ia.

wherein R¹, R⁴, R⁶, Q, m, n and p are as described above.

This invention relates to both the R and S stereoisomers of thebenzodioxan methylamines as well as to mixtures of the R and Sstereoisomers. Throughout this application, the name of the product ofthis invention, where the absolute configuration of the compounds of theinvention is not indicated, is intended to embrace the individual R andS enantiomers as well as mixtures of the two. In some embodiments of thepresent invention the S configuration of the2-aminomethyl-2,3-dihydro-1,4-benzodioxan moiety is preferred. Certainof the compounds of this invention (i.e., m does not equal n) containtwo stereogenic centers and thus may exist as diastereomers. Thisinvention relates to both diastereomers, as well as to mixtures ofdiastereomers For certain of the compounds of the invention (i.e., X andY form an imidazole), tautomeric forms may exist. This application thusencompasses all tautomeric forms of compounds of the present invention.

Where a stereoisomer is preferred, it may, in some embodiments beprovided substantially free of the corresponding enantiomer. Thus, anenantiomer substantially free of the corresponding enantiomer refers toa compound which is isolated or separated via separation techniques orprepared free of the corresponding enantiomer. “Substantially free,” asused herein, means that the compound is made up of a significantlygreater proportion of one stereoisomer. In preferred embodiments, thecompound is made up of at least about 90% by weight of a preferredstereoisomer. In other embodiments of the invention, the compound ismade up of at least about 99% by weight of a preferred stereoisomer.Preferred stereoisomers may be isolated from racemic mixtures by anymethod known to those skilled in the art, including high performanceliquid chromatography (HPLC) and the formation and crystallization ofchiral salts or prepared by methods described herein. See, for example,Jacques, et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725(1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill,NY, 1962); Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972).

“Alkyl,” as used herein, refers to an aliphatic hydrocarbon chain andincludes straight and branched chains such as methyl, ethyl, n-propyl,isoproyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1to 3 carbon atoms.

“Alkanamido,” as used herein, refers to the group R—C(═O)—NH— where R isan alkyl group of 1 to 5 carbon atoms.

“Alkanoyl,” as used herein, refers to the group R—C(═O)— where R is analkyl group of 1 to 5 carbon atoms.

“Alkanoyloxy,” as used herein, refers to the group R—C(═O)—O— where R isan alkyl group of 1 to 5 carbon atoms.

“Alkanesulfonamido,” as used herein, refers to the group R—S(O)₂—NH—where R is an alkyl group of 1 to 6 carbon atoms.

“Alkanesulfonyl,” as used herein, refers to the group R—S(O)₂— where Ris an alkyl group of 1 to 6 carbon atoms.

“Alkoxy,” as used herein, refers to the group R—O— where R is an alkylgroup of 1 to 6 carbon atoms.

“Carboxamido,” as used herein, refers to the group NH₂—C(═O)—.

“Carboalkoxy,” as used herein refers to the group R—O—C(═O)— where R isan alkyl group of 1 to 5 carbon atoms.

“Halogen” (or “halo”), as used herein, refers to chlorine, bromine,fluorine, and iodine.

Pharmaceutically acceptable salts are those derived from such organicand inorganic acids as: acetic, lactic, citric, cinnamic, tartaric,succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic,pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic,benzoic, and similarly known acceptable acids.

Specific examples of compounds of Formula I are:

-   2-[3-(5-Fluoro-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;-   2-[3-(5-Fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;-   2-[3-(6-Fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;-   2-[3-(1H-Indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;-   2-[3-(5-Fluoro-1-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;-   2-({4-[(6-Fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;-   2-({4-[(6-Fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;-   1-[(1-{[8-Methyl-2,3-dihydro[1,4]-dioxino[2,3-f]quinolin-2-yl]methyl)pipendin-4-yl]-1H-indole-6-carbonitrile;-   2-[3-(6-Fluoro-indol-1-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;-   2-{3-[2-(6-Fluoro-indol-1-yl)-ethyl]-azetidin-1-ylmethyl}-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;-   1-{2-[1-(8-Methyl-2,3-dihydro-[1,4]-dioxino[2,3-f]quinolin-2-ylmethyl)-azetidin-3-yl]-ethyl}-1H-indole-6-carbonitrile;    and-   8-Methyl-2-[3-(5-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

Compounds of the present invention are suitably prepared in accordancewith the following general description and specific examples. Variablesused are as defined for Formula I, unless otherwise noted. Specifically(Scheme 1), the appropriately substituted azaheterocycle (2) is combinedwith a suitably substituted benzodioxan methyltosylate or bromide (1) ina solvent such as dimethyl sulfoxide and heated to a temperature of70-100° C. for several hours as illustrated below. Alternatively, theappropriately substituted azaheterocycle may be acylated with a suitablysubstituted benzodioxan carboxylic acid chloride, and the resultingamide reduced to the amine with a suitable reducing agent such aslithium aluminum hydride or borane/THF. The azaheterocycle may also becombined with a suitably substituted benzodioxan carboxaldehyde in thepresence of a reducing agent such as sodium cyanoborohydride.

The benzodioxan methyltosylates and halides (1) are known compounds orthey may be prepared from the appropriately substituted salicylaldehydesby the method (a) described in Scheme 2 below. The salicylaldehyde (3)is alkylated with an epihalohydrin or glycidyl arylsulfonate in thepresence of a suitable base. The aldehyde moiety is then converted to aphenol by a Baeyer-Villager procedure and cyclization to the benzodioxanmethanol (5) effected by treatment with a base such as potassiumcarbonate. The alcohol is elaborated to a tosylate (1) by treatment withp-toluenesulfonyl chloride and a tertiary amine base or to a bromide bytreatment. Alternatively (b), the substituted salicylaldehyde (6) may beprotected with a suitable protecting group such as benzyl and thealdehyde (7) converted to a phenol (8) as described above. Followingelaboration of the phenol to the glycidyl ether (9) by treatment with anepihalohydrin or glycidyl arylsulfonate, deprotection and cyclizationare effected in a single step via a transfer hydrogenation in thepresence of sodium bicarbonate. The bromide or tosylate is prepared asdescribed above. Or the benzodioxan methylbromide may be prepared from asuitably substituted guaiacol (10) by procedure (c) shown above. Theguiacol is alkylated with a glycidyl arylsulfonate or an epihalohydrinas described above. The methyl ether (11) is then cleaved by treatmentwith 48% HBr; this also converts the epoxide to a bromohydrin (12).Cyclization directly to the benzodioxan methylbromide (1) is effected bythe Mitsonobu procedure.

The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethylamines of theinvention in which R⁴ is H are alternatively prepared as illustrated inScheme 3 below. Specifically, the appropriately substitutednitroguaiacol (13) is alkylated with allyl bromide in the presence of asuitable base such as sodium hydride and then demethylated by a reagentsuch as sodium hydroxide. The resulting 4-nitro-2-allyloxyphenol (15) isthen alkylated with glycidyl tosylate or an epihalohydrin in thepresence of a base such as sodium hydride and heated in a high boilingsolvent such as mesitylene or xylene to effect both rearrangement of theallyl group and cyclization of the dioxan ring. The resulting primaryalcohol (17), is converted to the tosylate by reaction withp-toluenesulfonyl chloride in the presence of a tertiary amine orpyridine, or alternatively to a halide by reaction with carbontetrabromide or carbon tetrachloride in combination withtriphenylphosphine. The allyl side chain is then isomerized by treatmentwith catalytic bis-acetonitrile palladium (II) chloride in refluxingmethylene chloride or benzene. Allylic oxidation of 18 with seleniumdioxide in refluxing dioxane/water gives the o-nitrocinnamaldehyde,which upon reduction with iron in acetic acid cyclizes to the2,3-dihydro-1,4-dioxino[2,3-f]quinoline-2-methyltosylate (19) or halide.Replacement of the tosylate or halide with the appropriately substitutedazaheterocycles in some high boiling solvent such as dimethyl sulfoxidegives the title compounds of the invention.

The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethylamines of theinvention in which R⁴ is alkyl may be prepared from the nitro olefindescribed above in the following manner (Scheme 4). The rearrangedolefin (18) is treated sequentially with ozone and a tertiary amine orwith osmium tetroxide and sodium periodate to give theo-nitrobenzaldehyde (20). Condensation with the appropriatetriphenylphosphorylidene ketone under Wittig conditions gives theo-nitrocinnamyl ketone (21), which upon reduction by iron in aceticacid, cyclizes to the corresponding2,3-dihydro-1,4-dioxino[2,3-f]quinoline-2-methyltosylate (22).Replacement of the tosylate with the appropriately substitutedazaheterocycles as above gives the title compounds of the invention.Substitution of trimethyl phosphonoacetate for thetriphenylphosphorylidene ketone in the Wittig procedure above, followedby reduction of the nitro group with tin (II) chloride and cyclizationin acid gives the compounds of the invention in which R⁴ is hydroxy.Treatment of the hydroxy derivative with an inorganic acid chloride suchas phosphoryl chloride or bromide gives the compounds of the inventionin which R⁴ is halo. Substitution of diethyl cyanomethylphosphonate forthe tripheriylphosphorylidene ketone in the Wittig procedure above,followed by reduction of the nitro group with tin (II) chloride andcyclization in acid gives the compounds of the invention in which R⁴ isamino.

Compounds of the invention in which R¹ is attached to position 6 of the2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethylamines may bealternatively prepared by a variation of the Skraup quinoline synthesisaccording to Scheme 5 below. The appropriately substituted benzodioxanmethyltosylate (23) is nitrated under standard conditions with nitricacid in a solvent such as dichloroethane and the resulting nitrocompound (24) reduced by treatment with hydrogen in the presence of acatalyst such as platinum on sulfide carbon. Treatment of the resultinganiline (25) with acrolein in the presence of hydrogen chloride and anoxidant such as p-chloranil or naphthoquinone gives the corresponding2,3-dihydro-1,4-dioxino[2,3-f]quinoline (26). Replacement of thetosylate with the appropriately substituted azaheterocycles as abovegives the title compounds of the invention.

The 2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines of theinvention are prepared as illustrated below (Scheme 6). Theo-nitrobenzaldehyde (20) described above is converted to the oxime (27)by treatment with hydroxylamine hydrochloride in the presence of asuitable base such as sodium-acetate and the nitro group reduced to theamine by hydrogenation over palladium on carbon. Cyclization to thequinazoline N-oxide is effected by treatment at reflux with theappropriate ortho ester according to the method of Ostrowski(Heterocycles, vol. 43, No. 2, p. 389, 1996). The quinazoline N-oxidemay be reduced to the quinazoline (28) by a suitable reducing agent suchas hydrogen over Raney-nickel. Alternatively, an extended period ofreflux in the ortho ester gives the reduced quinazoline directly via adisproportionation reaction and the2,3-dihydro-1,4-dioxino[2,3-f]quinazoline-2-methyltosylate or halide maybe isolated by column chromatography. Replacement of the tosylate orhalide with the appropriately substituted azaheterocycles in some highboiling solvent such as dimethyl sulfoxide gives the title compounds ofthe invention.

The 2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines of theinvention may be alternatively prepared from the rearranged olefindescribed above by the method outlined in Scheme 7 below. The nitroolefin (18) is first reduced to the aniline by treatment with a suitablereducing agent such as stannous chloride dihydrate in refuxing ethylacetate and the resulting amine acylated with the appropriate acylhalide or anhydride. The olefin (29) is then converted to the aldehyde(30) by cleavage with catalytic osmium tetroxide in the presence ofexcess sodium periodate. Cyclization directly to the2,3-dihydro-1,4-dioxino[2,3-f]quinazoline-2-methyltosylate (28) orhalide is effected by treatment of the amido aldehyde (30) with ammoniaand replacement of the tosylate or halide with the appropriatelysubstituted azaheterocycles in some high boiling solvent such asdimethyl sulfoxide as described above gives the title compounds of theinvention.

The 2,3-dihydro-1,4-dioxino[2,3-f]quinoxalin-2-ylmethylamines of theinvention are prepared as illustrated in Scheme 8 below. Theo-nitrobenzaldehyde (20) described above is oxidized to theo-nitrobenzoic acid (31) by a suitable oxidant such as chromium trioxide(Jones' oxidation) or sodium chlorite and the acid converted to theo-nitroaniline (32) with diphenylphosphoryl azide (DPPA) in the presenceof a tertiary base such as diisopropylethylamine. Reduction of theresulting nitroaniline to the diamine (33) with hydrogen and palladiumon carbon and cyclization by treatment with the appropriate dicarbonylcompound (for example, glyoxal, 2,3-butanedione, 3,4-hexanedione) givesthe 2,3-dihydro-1,4-dioxino[2,3-f]quinoxaline-2-methyltosylate (34) orhalide. Replacement of the to syiate or halide with the appropriatelysubstituted azaheterocycles in some high boiling solvent such asdimethyl sulfoxide gives the title compounds of the invention.

The o-nitrobenzaldehyde (20) used in the chemistry described above maybe alternatively prepared as shown in scheme 9 below. The appropriatemono-allylated catechol (35) is elaborated with glycidyl tosylate asdescribed above and rearranged in refluxing mesitylene. Cyclization tothe benzodioxan methanol (37) is effected by treatment with sodiumbicarbonate in ethanol and the alcohol is converted to the tosylate (38)or halide as described above. After rearrangement of the double bond bytreatment with catalytic bis-acetonitrile palladium (II) chloride inrefluxing methylene chloride and cleavage with ozone or osmiumtetroxide/sodium periodate as described above, the resulting aldehyde(39) is regioselectively nitrated with a combination of nitric acid andtin (IV) chloride.

The 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethylamines ofthe invention are prepared as illustrated in Scheme 10 below. The amidoolefin (29) described in Scheme 7 is cleaved to the correspondingo-amidobenzaldehyde (30) by treatment with catalytic osmium tetroxide inthe presence of sodium periodate. The aldehyde is converted to thephenol (40) by treatment with meta-chloroperoxybenzoic acid in aBaeyer-Villager reaction and cyclization to the7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (41) is effected bytreatment at reflux with an appropriate dehydrating agent such as anortho ester or an acid catalyst such as p-toluenesulfonic acid.Replacement of the tosylate or halide with the appropriately substitutedazaheterocycles in some high boiling solvent such as dimethyl sulfoxidegives the title compounds of the invention.

Alternatively (Scheme 11), the nitro olefin (18) may be reduced with tin(II) chloride as described in Scheme 7 above and protected with asuitable protecting group such as carbobenzoxy (Cbz) before the olefinis cleaved to the aldehyde (43) by treatment with osmiumtetroxide/sodium periodate and the aldehyde converted to a phenol (44)by the Baeyer-Villager procedure. Deprotection by treatment withhydrogen over palladium on carbon gives the o-aminophenol, (45) which iscyclized to the 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (41) bytreatment with the appropriate ortho ester, carboxylic acid oranhydride. Treatment of the o-aminophenol with cyanogen bromide orchloride or a suitably substituted carbamoyl chloride leads to compoundsof the invention in which R⁴ is amino. Treatment of the o-aminophenolwith carbonyl diimidazole gives the oxazolone that leads to compounds ofthe invention in which R⁴ is halo via treatment with an inorganicanhydride such as phosphoryl chloride or bromide. Replacement of thetosylate with the appropriately substituted azaheterocycles as abovegives the title compounds of the invention.

Compounds of the invention in which R¹ is hydrogen and R⁴ is alkyl aremost conveniently prepared according to scheme 12 below. The appropriate2′,3′,4′-trihydroxyacylphenone (46) is regioselectively alkylated withglycidyl tosylate or an epihalohydrin in the presence of a base such assodium carbonate to give the corresponding7-acyl-8-hydroxybenzodioxan-2-methanol (47). Following conversion of theketone to the oxime (48) by reaction with hydroxylamine hydrochlorideand sodium acetate, cyclization to the oxazole (49) is effected bytreatment with phosphoryl chloride in the appropriate dimethylalkanoicacid amide. The resulting7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalene-8-methanol isconverted to the tosylate (50) by treatment with p-toluenesulfonylchloride in pyridine and combined with the appropriate azaheterocyclesas described above to give the title compounds of the invention.

The 7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalenes of theinvention are prepared as illustrated in Scheme 13 below. The diamine 33described in Scheme 8 is cyclized by treatment at reflux with theappropriate carboxylic acid to give the imidazole (51). Refluxing thediamine dihydrochloride in higher boiling carboxylic acids occasionallycauses replacement of a tosylate group with a chloride. Replacement ofthe tosylate or halide with the appropriately substituted piperidine insome high boiling solvent such as dimethyl sulfoxide gives the7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalenes of theinvention in which R⁷ is hydrogen, perfluoroalkyl, or alkyl. Treatmentof the diamine described above with cyanogen bromide or chloride or asuitably substituted carbamoyl chloride leads to compounds of theinvention in which R⁷ is amino. Treatment of the diamine with carbonyldiimidazole gives the imidazolone that leads to compounds of theinvention in which R⁷ is halo via treatment with an inorganic anhydridesuch as phosphoryl chloride or bromide. Replacement of the tosylate withthe appropriately substituted azaheterocycles as above gives the titlecompounds of the invention.

The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the invention areprepared as illustrated in Scheme 14 below. Specifically, the primaryalcohol (17) from the Claisen rearrangement described in Scheme 3 isconverted to the tosylate (52) by reaction with p-toluenesulfonylchloride in the presence of a tertiary amine or pyridine, oralternatively to a halide by reaction with carbon tetrabromide or carbontetrachloride in combination with triphenylphosphine. The allyl sidechain is then cleaved to the aldehyde (53) by treatment with ozone atlow temperature, followed by work-up with a tertiary base such asdiisopropylethylamine or triethylamine, or by treatment with catalyticosmium tetroxide and sodium periodate. Reduction of the nitro group withhydrogen over platinum oxide leads directly to formation of the indole(54) in which R⁸ is hydrogen. Alternatively, the aldehyde may be treatedwith an appropriate alkyl Grignard reagent or with trifluoromethyltrimethylsilane in the presence of cesium fluoride, then oxidized to aketone with a suitable oxidant such as pyridinium chlorochromate (PCC)or the Swern reagent and reduced with hydrogen over platinum oxide togive the indoles in which R⁸ is alkyl or trifluoromethyl. Replacement ofthe tosylate or halide with the appropriately substitutedazaheterocycles in some high boiling solvent such as dimethyl sulfoxidegives the title compounds of the invention.

The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the invention mayalternatively be prepared from nitroaldehyde 20 by the followingprocedure (Scheme 15). The o-nitrobenzaldehyde (20) is condensed withthe appropriate nitroalkane in the presence of a suitable base catalystto yield the corresponding o,β-dinitrostyrene (55). Reduction of bothnitro groups with hydrogen over palladium on carbon is accompanied bycyclization to form the indole (56). Replacement of the tosylate withthe appropriately substituted azaheterocycles as above gives the titlecompounds of the invention.

The compounds of the invention may be resolved into their enantiomers byconventional methods or, preferably, the individual enantiomers may beprepared directly by substitution of (2R)-(−)-glycidyl3-nitrobenzene-sulfonate or tosylate (for the S benzodioxan methanamine)or (2S)-(+)-glycidyl 3-nitrobenzene-sulfonate or tosylate (for the Renantiomer) in place of epihalohydrin or racemic glycidyl tosylate inthe procedures above.

In yet another method, the heterocycle-fused benzodioxans of the presentinvention may be prepared in accordance with Scheme 16. The synthesis ofcompound I is comprised of steps that begin with halogenation of 57where R′ is alkyl of 1-6 carbon atoms, with reagents such asN-halosuccinimide in acetonitrile to give 58 (where Hal is halogen suchas Br, Cl or I). Deprotecting 58 with Lewis acids such as borontribromide, boron trichloride, aluminum trichloride, ferric chloride, ortrimethylsilyl iodide in a suitable solvent such as methylene chloride,or with strong protic acids such as HBr and HCl gives the salt 59. Freebase 59 may be obtained by neutralization with an Amberlyst A-21 resinslurry in polar solvents such as ethanol or methanol.

Alkylation of 59, either as the free base or as the salt, with benzyl orsubstituted benzyl protected glycidyl ethers

where R″ is benzyl, substituted benzyl such as 4-bromobenzyl,3,4-dimethoxybenzyl, 2- or 4-nitrobenzyl, or 4-methoxybenzyl) insuitable polar solvents such as DMSO, DMF, or DMA in the presence ofbases such as sodium carbonate, potassium carbonate, or triethylaminegives 60. 60 was then cyclized using palladium catalysts such astris(dibenzylideneacetone)dipalladium,tetrakis(triphenylphosphine)palladium, or palladium acetate with ligandsfrom the group consisting of (±) BINAP and separate enantiomers thereof,(±) Tol-BINAP and separate enantiomers thereof;1-1′-bis(diphenylphosphino)ferrocene, 1,3-bis(diphenylphosphino)propane,and 1,2bis(diphenyl-phosphino)ethane in the presence of bases such asNaH, LiH, KH, potassium carbonate, sodium carbonate, titanium carbonate,cesium carbonate, potassium t-butoxide or potassium phosphate tribasicin suitable solvent such as toluene, or alternatively, with coppercatalyst such as copper iodide in the presence of bases such NaH, LiH,KH in a suitable solvent such as toluene to afford 61.

Deprotection of quinoline 61 with Lewis acids such as boron tribromide,boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyliodide in a suitable solvent such as methylene chloride, or with strongprotic acids such as HBr and HCl or under reductive cleavage conditionsusing Pd catalyst and hydrogen transfer reagents such as hydrogen,cyclohexene, methyl cyclohexene, or ammonium formate gives theheterocycle-fused benzodioxanmethanol 62. The hydroxyl moiety of 62 canbe activated with an aryl- or alkylsulfonyl chloride such asp-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or4-nitrobenzenesulfonyl chloride, or 2- or 4-bromobenzenesulfonylchloride in the presence of bases such as triethylamine or pyridine insuitable solvents such as methylene chloride, THF, or toluene to afford65 where R′″ is a sulfonate such as p-toluenesulfonate,methanesulfonate, 2-, 3-, or 4-nitrobenzenesulfonate, or 2- or4-bromobenzenesulfonate. The final coupling of 63 with azaheterocyclesappropriate to the invention, in the presence of bases such as Hünig'sbase (diisopropylethylamine), potassium carbonate, or sodium carbonatein polar solvents such as THF, dioxane, DMSO, DMF, or DMA affords thecompounds of the invention I.

The phenols, guaiacols, catechols, 2′,3′,4′-trihydroxyacylphenones andbenzodioxan methyltosylates appropriate to the above chemistry are knowncompounds or can be prepared by one schooled in the art. Theazaheterocycles are known compounds or they can readily be prepared byone schooled in the art using the procedures outlined by Baker et al. inWO 94/02477, Gil et. al. In WO 94/24125 or Arora et. al. in WO 00/38677.The azaheterocycles in which Q is a) and m, n and p are 1 mayalternatively be prepared according to the method outlined in Scheme 17.The suitably protected azetidinone (64) is converted to the homologousaldehyde (66) by a two step procedure involving Wittig reaction of 64with the betaine generated from (methoxymethyl)triphenylphosphoniumchloride and sodium hydride, followed by hydrolysis of the resultingenol ether (65) with aqueous acid. The aldehyde (66) is reacted with asuitably substituted indole under the influence of a base such as sodiumhydroxide to give the condensation product (67). Reduction withtriethylsilane, followed by deprotection by transfer hydrogenation givesthe indolemethylazetidine (68) useful for the preparation of certain ofthe compounds of the invention.

The azaheterocycles in which Q is b) may alternatively be preparedaccording to the method outlined in Scheme 18. The suitably protected (Prepresents a protecting group such as carbobenzyloxy, t-butoxycarbonyl,benzhydryl, benzyl, etc.) heterocyclylalkyl halide, tosylate ormethanesulfonate 69, in which L represents the leaving group, iscombined with the appropriately substituted indole and heated to 40-100°C. in the presence of a base such as sodium hydride in a polar solventsuch as N,N-dimethylformamide or methylsulfoxide. The resultingalkylated indole 70 is then deprotected by the appropriate means, forexample hydrogenolysis over palladium on carbon for carbobenzyloxy,benzyl or benzhydryl or treatment with acid for t-butoxycarbonyl, togive the azaheterocycles useful for the preparation of certain of thecompounds of the invention.

A protocol similar to that used by Cheetham et al. (Neuropharmacol.32:737, 1993) was used to determine the affinity of the compounds of theinvention for the serotonin transporter. The compound's ability todisplace ³H-paroxetine from male rat frontal cortical membranes wasdetermined using a Tom Tech filtration device to separate bound fromfree ³H-paroxetine and a Wallac 1205 Beta Plate® counter to quantifybound radioactivity. K_(i)'s thus determined for standard clinicalantidepressants are 1.96 nM for fluoxetine, 14.2 nM for imipramine and67.6 nM for zimelidine. A strong correlation has been found between³H-paroxetine binding in rat frontal cortex and ³H-serotonin uptakeinhibition.

High affinity for the serotonin 5-HT_(1A) receptor was established bytesting the claimed compound's ability to displace [³H] 8-OHDPAT(dipropylaminotetralin) from the 5-HT_(1A) serotonin receptor followinga modification of the procedure of Hall et al., J. Neurochem. 44, 1685(1985) which utilizes CHO cells stably transfected with human 5-HT_(1A)receptors. The 5-HT_(1A) affinities for the compounds of the inventionare reported below as K_(i)'s.

Antagonist activity at 5-HT_(1A) receptors was established by using a³⁵S-GTPγS binding assay similar to that used by Lazareno and Birdsall(Br. J. Pharmacol. 109: 1120, 1993), in which the test compound'sability to affect the binding of ³⁵S-GTPγS to membranes containingcloned human 5-HT_(1A) receptors was, determined. Agonists produce anincrease in binding whereas antagonists produce no increase but ratherreverse the effects of the standard agonist 8-OHDPAT. The testcompound's maximum inhibitory effect is represented as the I_(max),while its potency is defined by the IC₅₀.

The results of the three standard experimental test procedures describedin the preceding three paragraphs were as follows:

5-HT_(1A) 5-HT Transporter 5-HT_(1A) Receptor Function Affinity AffinityCompound KI (nM) KI (nM) IC₅₀ (nM) (I_(max)) Example 1 2.50 1.29  59.5(73.7) Example 2 3.30 15.30 552.4 (100)  Example 3 3.40 15.12 666.4(100)  Example 4 9.20 0.56  37.2 (76.4) Example 5 16.70 0.72  34.5(96.3) Example 6 9.55 1.01 241.8 (85.5) Example 7 15.18 1.61 208.1(81.5) Example 8 6.56 0.60 243.2 (100)  Example 9 55.00 0.11 Example 101.90 4.26 342.8 (80.0) Example 11 1.52 2.86 250.9 (85.0) Example 12 1.04 38.6 (89.5

Like the antidepressants fluoxetine, paroxetine, and sertraline, thecompounds of this invention have the ability to potently block thereuptake of the brain neurotransmitter serotonin. They are thus usefulfor the treatment of diseases commonly treated by the administration ofserotonin selective reuptake inhibitor (SSRI) antidepressants, such asdepression (including but not limited to major depressive disorder,childhood depression and dysthymia), anxiety, panic disorder,post-traumatic stress disorder, premenstrual dysphoric disorder (alsoknown as premenstrual syndrome), attention deficit disorder (with andwithout hyperactivity), obsessive compulsive disorders (including butnot limited to trichotillomania), obsessive compulsive spectrumdisorders (including but not limited to autism), social anxietydisorder, generalized anxiety disorder, obesity, eating disorders suchas anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine andalcohol addiction, sexual dysfunction (including but not limited topremature ejaculation), incontinence (including, but not limited tofecal incontinence, urge incontinence, overflow incontinence, passiveincontinence, reflex incontinence, stress urinary incontinence urinaryexertional incontinence and urinary incontinence), and pain (including,but not limited to migraine, chronic back pain, phantom limb pain,neuropathic pain such as diabetic neuropathy, and post herpeticneuropathy) and related illnesses. Moreover, the compounds of thisinvention have potent affinity for and antagonist activity at brain5HT_(1A) serotonin receptors. Recent clinical trials employing drugmixtures (e.g., fluoxetine and pindolol) have demonstrated a more rapidonset of antidepressant efficacy for a treatment combining SSRI activityand 5HT_(1A) antagonism (Blier and Bergeron, 1995; F. Artigas et. al.,1996; M. B. Tome et. al., 1997). The compounds of the invention are thusexceedingly interesting and useful for treating depressive illnesses.

Thus the present invention provides methods of treating, preventing,inhibiting or alleviating each of the maladies listed above in a mammal,preferably in a human, the methods comprising providing apharmaceutically effective amount of a compound of this invention to themammal in need thereof.

Also encompassed by the present invention are pharmaceuticalcompositions for treating or controlling disease states or conditions ofthe central nervous system comprising at least one compound of FormulaI, mixtures thereof, and or pharmaceutical salts thereof, and apharmaceutically acceptable carrier therefore. Such compositions areprepared in accordance with acceptable pharmaceutical procedures, suchas described in Remington's Pharmaceutical Sciences, 17th edition, ed.Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985).Pharmaceutically acceptable carriers are those that are compatible withthe other ingredients in the formulation and biologically acceptable.

The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substancesthat may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid that is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes, and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensionsemulsions, syrups, and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers, or osmo-regulators. Suitable examples of liquid carriersfor oral and parenteral administration include water (particularlycontaining additives as above, e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions that are sterile solutions orsuspensions can be administered by, for example, intramuscular,intraperitoneal, or subcutaneous injection. Sterile solutions can alsobe administered intravenously. Oral administration may be either liquidor solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

The amount provided to a patient will vary depending upon what is beingadministered, the purpose of the administration, such as prophylaxis ortherapy, and the state of the patient, the manner of administration, andthe like. In therapeutic applications, compounds of the presentinvention are provided to a patient already suffering from a disease inan amount sufficient to cure or at least partially ameliorate thesymptoms of the disease and its complications. An amount adequate toaccomplish this is defined as a “therapeutically effective amount.” Thedosage to be used in the treatment of a specific case must besubjectively determined by the attending physician. The variablesinvolved include the specific condition and the size, age, and responsepattern of the patient. Generally, a starting dose is about 5 mg per daywith gradual increase in the daily dose to about 150 mg per day, toprovide the desired dosage level in the human.

Provide, as used herein, means either directly administering a compoundor composition of the present invention, or administering a prodrug,derivative or analog that will form an equivalent amount of the activecompound or substance within the body.

The present invention includes prodrugs of compounds of Formula I andIa. “Prodrug,” as used herein, means a compound which is convertible invivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I.Various forms of prodrugs are known in the art, for example, asdiscussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);Widder, et al. (ed.), Methods in Enymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen, et al., (ed). “Design and Application ofProdrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992)Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); andHiguchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975).

The following examples illustrate the production of representativecompounds of this invention.

Intermediate 1 3-Allyloxy-4-methoxynitrobenzene

97.5 g (0.51 mole) of the sodium salt of 5-nitroguaiacol was dissolvedin one liter of DMF and 1.5 equivalents of allyl bromide added. Thereaction was heated to 65° C. for two hours, after which time much ofthe dark color had discharged and tlc (1:1 CH₂Cl₂/hexane) indicated lossof starting material. The solvent was concentrated in vacuum and theresidue washed with water. The product was isolated by filtration anddried in a vacuum. This gave 112 g of pale yellow solid. A samplerecrystallized from methanol, gave m.p. 93-94° C.

Intermediate 2 2-Allyloxy-4-nitrophenol

To one liter of dimethyl sulfoxide was added 750 mL of 2 N aqueoussodium hydroxide and the mixture was heated to 65° C. The pale yellowsolid 3-allyloxy-4-methoxynitrobenzene prepared above was added inportions over a 30-minute period and then the temperature was raised to95° C. and maintained for 3 hours, after which time the startingmaterial had been consumed. The mixture was allowed to cool and pouredinto a mixture of 1 L ice and 1 L 2 N HCl. 73 Grams of crude buthomogeneous (by tlc 1:1 CH₂Cl₂/hexane) desired product was isolated as alight brown solid by filtration. This material was subsequentlydissolved in 1:1 hexane/methylene chloride and filtered through silicagel to give 68 g of pale yellow solid, which, when recrystallized fromethyl/acetate/hexane, gave m.p. 61-62° C. The aqueous mother liquorsfrom the initial crystallization above were extracted with 2 L of ethylacetate. This was dried over sodium sulfate, filtered, and evaporated toa dark oil. Column chromatography on silica with 1:1 CH₂Cl₂/hexane gavean additional 12 g of the title compound as a yellow solid. Elution with2% MeOH in CHCl₃ gave 12 g of a dark oil that slowly crystallized invacuum. This proved to be the Claisen product, 3-allyl-4-nitrocatechol.

Intermediate 3 2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane

20 g (0.50 mole) of 60% NaH/mineral oil was placed in a two-liter flaskand washed with 500 mL of hexane. 1 L of DMF was added, followed by 77 g(0.40 mole) of the 2-allyloxy-4-nitrophenol prepared in the previousstep. Addition of the phenol was performed in portions under argon.After stirring the mixture for 30 minutes at room temperature underargon, 108 g (0.48 moles) of (R)-glycidyl tosylate was added and themixture heated at 70-75° C. under nitrogen overnight. Upon cooling, theDMF was removed in vacuum and replaced with one liter of methylenechloride. This was washed with 500 mL portions of 2 N HCl, saturatedsodium bicarbonate and saturated brine and dried over sodium sulfate.The mixture was filtered, concentrated to an oil in vacuum and columnchromatographed on silica gel using 1:1 hexane/methylene chloride aseluent. This gave 43 g of product contaminated with traces of the twostarting materials, followed by 21 g of pure product as a pale yellowsolid. The impure material was recrystallized from 1.2 L of 10% ethylacetate/hexane to give 34 g of pure (homogeneous on silica gel tlc with1:1 hexane/methylene chloride)(R)-2-(2-allyloxy-4-nitrophenoxymethyl)-oxirane (m.p. 64° C.).

Elemental Analysis for: C₁₂H₁₃NO₅ Calc'd: C, 57.37; H, 5.21; N, 5.58Found: C, 57.50; H, 5.21; N, 5.43

Intermediate 4(8-Allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol

(R)-2-(2-Allyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80 mmoles)prepared as above was heated at 155° C. in mesitylene for 24 hours undernitrogen. Filtration of the black solid that formed gave 1.5 g of verypolar material. Evaporation of the solvent in vacuum followed by columnchromatography on silica gel with methylene chloride as eluent gave 10 gof recovered starting material and 7.5 g of the desired rearranged(S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol, whichslowly crystallized on standing in vacuum (m.p. 67° C.). The yield basedon recovered starting material is 75%.

Elemental Analysis for: C₁₂H₁₃NO₅ Calc'd: C, 57.37; H, 5.21; N, 5.58Found: C, 57.26; H, 5.20; N, 5.35

Intermediate 5 Toluene-4-sulfonic acid8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester

9.55 g (38.0 mmole) of(S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl)-methanol wasdissolved in 465 mL of pyridine, 29.0 g (152 mmole) of p-toluenesulfonylchloride was added and the mixture stirred at room temperature undernitrogen overnight. Water was then added to quench the excess tosylchloride and the solvent was removed in vacuum and replaced withmethylene chloride. This solution was washed with 2 N HCl, withsaturated sodium bicarbonate, and with saturated brine, and dried overmagnesium sulfate. Filtration, evaporation in vacuum and columnchromatography on silica gel with 1:1 hexane/methylene chloride aseluent gave 12.6 g (92%) of toluene-4-sulfonic acid(R)-allyl-7-nitro-2,3-benzo(1,4)dioxin-2-ylmethyl ester, which slowlycrystallized to a tan solid (m.p. 60-62° C.) upon standing.

Elemental Analysis for: C₁₉H₁₉NO₇S Calc'd: C, 56.29; H, 4.72; N, 3.45Found: C, 56.13; H, 4.58; N, 3.44

Intermediate 6{7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

To a solution of 10.0 g (24.0 mmole) of(R)-[8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methylbenzenesulfonate in 700 mL of benzene was added 1.03 g ofbis(acetonitrile)dichloropalladium (II) and the mixture was refluxedunder nitrogen for 48 hours. The catalyst was then removed byfiltration, and the filtrate concentrated in vacuum to a brown oil.Column chromatography on silica gel with methylene chloride as eluentgave 7.2 g of the title compound as a mixture of E and Z isomers. Asample of{(2R)-7-nitro-8[(E)-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate was obtained as a yellow solid (m.p. 105-106°C.) by evaporation of a pure E isomer-containing fraction.

Elemental Analysis for: C₁₉H₁₉NO₇S Calc'd: C, 56.29; H, 4.72; N, 3.45Found: C, 56.12; H, 4.64; N, 3.39

Intermediate 7{7-Nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

{(2R)-7-nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methyl benzenesulfonate (6.15 g, 15.2 mmole) was dissolved in 180 mLof dioxane. Selenium dioxide (4.20 g, 37.9 mmole) was then added,followed by 0.70 mL of water. The heterogeneous mixture was heated atreflux under nitrogen for 5 hours. Upon cooling, the reaction wasfiltered and concentrated in vacuum to yield a dark yellow solid. Thiswas dissolved in minimal ethyl acetate and column chromatographed onsilica gel using 30% ethyl acetate in hexane as eluent to give 5.75 g ofthe (R)-enantiomer of the title compound as a light yellow solid (m.p.138-140° C.).

Elemental Analysis for: C₁₉H₁₇NO₈S Calc'd: C, 54.41; H, 4.09; N, 3.34Found: C, 54.10; H, 3.85; N, 3.31

Intermediate 8 2,3-Dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl4-methylbenzenesulfonate

To a solution of{(2R)-7-nitro-8-[3-oxo-1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (3.50 g, 8.35 mmole) in 200 mL of aceticacid/ethanol (1:1) was added 2.35 g (42.1 mmole) of iron powder and themixture was heated at reflux under nitrogen for 8 hours. After thereaction was complete, 150 mL of water was added and the mixturefiltered through a pad of celite. The filtrate was neutralized withsaturated sodium bicarbonate and extracted with ethyl acetate. Theextract was dried over magnesium sulfate, filtered, and evaporated invacuum. The residue was column chromatographed on silica gel using agradient elution commencing with 20% ethyl acetate/hexane and endingwith 70% ethyl acetate/hexane to give 1.85 g of the (R)-enantiomer ofthe title compound as a yellow oil. ¹H-NMR (CDCl₃): doublet 8.8 δ (1 H);doublet: 8.2 δ (1 H); doublet 7.8 δ (2 H); doublet 7.6 δ (1 H);multiplet 7.35 δ (1 H); multiplet 7.25 δ (3 H); multiplet 4.6 δ (1 H);multiplet 4.3-4.4 δ (3 H); multiplet 4.2 δ (1 H); singlet 2.4 δ (3 H).

Intermediate 9 (8-Formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl4-methylbenzenesulfonate

{(2R)-7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methyl benzenesulfonate (10.5 g, 25.9 mmole) dissolved in 400 mL ofmethylene chloride was treated with excess ozone at −78° C.Diisopropylethylamine (11.5 mL, 66.0 mmole) was then added dropwise over30 minutes and the mixture allowed to come to room temperature and stirovernight under a nitrogen atmosphere. The mixture was then diluted to600 mL with methylene chloride, washed three times with 100 mL portionsof 2N HCl (aq), twice with 200 mL portions of saturated aqueous sodiumbicarbonate and with 200 mL of saturated brine. The solution was driedover magnesium sulfate, filtered and concentrated in vacuum to a crudebrown oil, which was column chromatographed on silica gel with 10%hexane/methylene chloride to give 7.52 g of the (R)-enantiomer of thetitle compound as a yellow solid. ¹H-NMR (CDCl₃): doublet 7.8 δ (2 H);doublet 7.62 δ (1 H); doublet 7.4 δ (2 H); doublet 7.0 δ (1 H);multiplet 4.4-4.6 δ (2 H); multiplet 4.2 δ (3 H); singlet 2.4 δ (3 H).

Intermediate 10{7-Nitro-8-[(E)-3-oxo-1-butenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate

To a solution of 3.00 g (7.37 mmole) of[(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methylbenzenesulfonate in 250 mL of toluene was added 2.90 g (9.10mmole) of 1-triphenylphosphorylidene-2-propanone. The mixture wasstirred at room temperature under nitrogen for 5 hours, during whichtime some product precipitated from solution. The solvent was removed invacuum and the crude residue was column chromatographed on silica gelwith methylene chloride as eluent to give 3.0 g of the (R)-enantiomer ofthe title compound as a yellow solid. ¹H-NMR (CDCl₃): doublet 7.8 δ (2H); doublet 7.6 δ (1 H); doublet 7.5 δ (2 H); doublet 7.4 δ (2 H);doublet 6.95 δ (1 H); doublet 6.6 δ (1 H); multiplet 4.5 δ (1 H);doublet of doublets 4.0 δ (1 H); multiplet 4.2 δ (3 H); singlet 2.45 δ(3 H); singlet 2.4 δ (3 H).

Intermediate 11(8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl)methyl4-methylbenzenesulfonate

To a solution of{(2R)-7-nitro-8-[(E)-3-oxo-1-butenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl4-methylbenzenesulfonate (3.40 g, 7.83 mmole) in 200 mL of aceticacid/ethanol (3:2) was added 2.25 g (40.2 mmole) of iron powder and themixture was heated at reflux under nitrogen for 8 hours. After thereaction was complete, 150 mL of water was added and the mixturefiltered through a pad of celite. The filtrate was neutralized withsaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The extract was dried over magnesium sulfate, filtered, and evaporatedin vacuum. The residue was column chromatographed on silica gel using agradient elution commencing with 20% ethyl acetate/hexane and endingwith 70% ethyl acetate/hexane to give 2.5 g of the (R)-enantiomer of thetitle compound as a yellow oil. ¹H-NMR (CDCl₃): doublet 8.1 δ (1 H);doublet 7.6 δ (2 H) doublet 7.45 δ (1 H); multiplet 7.2 δ (4 H);multiplet 4.6 δ (1 H); multiplet 4.3 δ (3 H); multiplet 4.1 δ (1 H);singlet 2.5 δ (3 H); singlet 2.4 δ (3 H).

Intermediate 12[7-Nitro-8-(2-oxoethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methylbenzenesulfonate

A solution of 4.2 g (10 mmole) of toluene-4-sulfonic acid(2R)-8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester in400 mL of methylene chloride was cooled in a dry ice/isopropanol bathand saturated with ozone. It was then purged with oxygen and 2.6 g (20mmole) of diisopropylethylamine added. The mixture was allowed to cometo room temperature and stirred under nitrogen for 24 hours. It was thenwashed with 300 mL portions of 2 N HCl (aq), water and saturated brine,dried over magnesium sulfate, filtered and concentrated in vacuum togive 3.8 g of the (R)-enantiomer of the title compound as a white solidone-quarter hydrate, m.p. 116-120° C.

Elemental Analysis for: C₁₈H₁₇NO₈S.0.25H₂O Calc'd: C, 52.49; H, 4.28; N,3.40 Found: C, 52.33; H, 3.92; N, 3.36

Intermediate 13 2,3-Dihydro-7H-[1,4]dioxino[2,3-e]indol-2-ylmethyl4-methylbenzenesulfonate

A mixture of 3.75 g (9.2 mmole) of[(2R)-7-nitro-8-(2-oxoethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl4-methylbenzenesulfonate and 3.0 g of platinum oxide in 50 mL of ethylacetate was treated with 45 psi of hydrogen on a Parr hydrogenationapparatus for 6 hours. The mixture was then filtered through celite andconcentrated in vacuum. The residue was column chromatographed on silicagel with first 10% hexane/methylene chloride, then 1% methanol/methylenechloride and finally 2% methanol/methylene chloride to give 1.50 g ofthe (R)-enantiomer of the title compound as a white solid one-quarterhydrate, m.p. 145° C.

Elemental Analysis for: C₁₈H₁₇NO₅S.0.25H₂O Calc'd: C, 59.41; H, 4.85; N,3.85 Found: C, 59.41; H, 4.57; N, 3.72

Intermediate 141-[5-Hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone

To a solution of 2′,3′,4′-trihydroxyacetophenone (10.6 g, 63.0 mmole) inDMF (75 mL) was added potassium carbonate (17.4 g, 126 mmole). After 5minutes (R)-glycidyl tosylate (9.67 g, 42.3 mmole) was added, then theheterogeneous mixture was heated to 70° C. for 3 hours. After removal ofthe solvent in vacuum, the residue was taken into water (800 mL) and wasthen extracted with ethyl acetate (4×300 mL). The combined organiclayers were dried over magnesium sulfate, filtered and evaporate todryness in vacuum. The crude brown oil thus obtained was columnchromatographed on silica gel with 40% hexane/ethyl acetate as eluent togive the (S)-enantiomer of the title compound as a yellow oil whichsolidifies upon standing (7.5 g, 78%). MS (ESI) m/z 223 (M−H)−.

Elemental Analysis for: C₁₁H₁₂O₅.0.10H₂O Calc'd: C, 58.46; H, 5.44Found: C, 58.02; H, 5.09

Intermediate 151-[5-Hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanoneoxime

A solution of hydroxylamine hydrochloride (2.38 g, 34.2 mmole) in 1:1ethanol/pyridine (100 mL) was added to a solution of1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone(1.92 g, 8.57 mmole) in ethanol (200 mL). It was then heated to refluxunder nitrogen for 5 hours. Upon cooling, the solvent was removed andreplaced with ethyl acetate. The solution was then washed with water(200 mL) and with aqueous 2N HCl (100 mL), dried over magnesium sulfate,filtered and evaporated in vacuum to give 1.89 g (93%) of the(S)-enantiomer of the title compound as a gray solid, m.p. 162° C., MS(ESI) m/z 240 (M+H)+.

Elemental Analysis for: C₁₁H₁₃NO₅.0.35H₂O Calc'd: C, 53.81; H, 5.62; N,5.71 Found: C, 53.51; H, 5.30; N, 5.58

Intermediate 16[2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methanol

3.03 g (12.6 mmole) of1-[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanoneoxime was dissolved in- a mixture of 1:3N,N-dimethylacetamide/acetonitrile (100 mL). The solution was cooled inan ice/water bath and a solution of phosphorus oxychloride (1.26 mL, 35mmole) in 1:3 N,N-dimethylacetamide/acetonitrile (30 mL) was added. Thereaction mixture was stirred under nitrogen over a period of 48 hours.It was then added to an ice cold, saturated solution of sodium acetate,extracted with ethyl acetate, dried over magnesium sulfate, filtered andevaporated in vacuum. The resulting crude oil was column chromatographedon silica gel with 60% hexane/ethyl acetate to remove impurities and theproduct eluted with 40% hexane/ethyl acetate. After evaporation of thesolvent in vacuum, 2.08 g (75%) of the (S)-enantiomer of the titlecompound was obtained as a white solid, m.p. 120° C. MS (ESI) m/z 222(M+H)+.

Elemental Analysis for: C₁₁H₁₁NO₄.0.20H₂O Calc'd: C, 58.77; H, 5.11; N,6.23 Found: C, 58.93; H, 4.91; N, 6.14

Intermediate 17[2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl4-methylbenzenesulfonate

To a solution of[(8S)-2-methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methanol(1.80 g, 8.14 mmole) in methylene chloride (100 mL) was addedp-toluenesulfonyl chloride (3.90 g, 20.4 mmole). The mixture was cooledin an ice bath and a solution of diisopropylethylamine (3.55 mL, 20.4mmole) in methylene chloride (20 mL) was then added dropwise, followedby 4-dimethylaminopyridine (0.65 g, 5.30 mmole). The solution wasallowed to warm to room temperature and was stirred under nitrogenovernight. The reaction was diluted to 500 mL in volume with methylenechloride, then washed with aqueous 2 N HCl (200 mL), with saturatedaqueous sodium bicarbonate (200 mL), and with brine (150 mL), dried overmagnesium sulfate, filtered and evaporated in vacuum to a yellow oil.The crude oil was column chromatographed on silica gel using methylenechloride to remove impurities and 3% methanol/methylene chloride toelute the (R)-enantiomer of the title compound, which becomes a whitesolid under vacuum (2.56 g, 84%), m.p. 123° C. MS (ESI) m/z 376 (M+H)+.

Elemental Analysis for: C₁₈H₁₇NO₆S.0.20 H₂O Calc'd: C, 57.04; H, 4.63;N, 3.70 Found: C, 56.75; H, 4.62; N, 3.51

Intermediate 18 5-Bromo-6-methoxy-2-methylquinoline

A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) inacetonitrile (1.77 L) was cooled to 0-3° C. followed by portion-wiseaddition of N-bromo-succinimidyl (200 g, 1.12 mol) over a period of 30minutes while maintaining the same temperature. The resulted brownslurry was warmed to ambient temperature and stirred for an additional 6h. The reaction was then quenched by a 10% NaHSO₃ solution (211 mL). Thereaction mixture was concentrated to a volume of 600 mL then slowlypoured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred at roomtemperature for 1 h then filtered, washed with water (2×1 L) and driedin a vacuum oven to give 253 g (98.6%) of the title compound as a brownsolid. R_(f)=0.39 (3:7) EtOAc:heptane; ¹H NMR (DMSO) δ 8.30 (d, J=6.5Hz, 1H), 7.98 (d, J=6.9 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.47 (d, J=6.5Hz, 1H), 4.02 (s, 3H), 2.66 (s, 3H);

Elemental Analysis for: C₁₁H₁₀NOBr Calc'd: C, 52.40; H, 3.97; N, 5.56Found: C, 52.13; H, 3.94; N, 5.61

Intermediate 19 5-Bromo-2-methyl-6-quinolinol

A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12 mol) in 48%HBr (135 mL) was heated to reflux for 7 h then cooled to 5° C. in 1 hourto give a brown and thick slurry. The slurry was stirred at 0-5° C. for1 hour then filtered, washed with EtOAc (2×50 mL) and dried in a vacuumoven to give 34.9 g (92%) of the hydrobromide of the title compound as abrown solid. ¹H NMR (DMSO) δ 8.26 (d, J=8.7 Hz, 1H), 7.85 (d, J=9.1 Hz,1H), 7.56 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 2.64 (s, 3H). Aslurry of the hydrobromide salt of 5-bromo-2-methyl-6-quinolinol (3.4 g,10.5 mmol) and Amberlyst A-21 ion-exchange resin (1.7 g, pre-washed withMeOH then dried in oven) in MeOH (35 mL) was stirred at room temperaturefor 3 h. The mixture was then filtered and concentrated in vacuo to give2.5 g (100%) of a yellow solid. R_(f)=0.36 (1:1) EtOAc:heptane; ¹H NMR(DMSO) δ 8.26 (d, J=8.4 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.47 (t, J=9.1Hz, 2H), 2.66 (s, 3H).

Intermediate 20(2S)-1-(Benzyloxy)-3-[(5-bromo-2-methyl-6-quinolinyl)oxy]-2-propanol

A solution of 5-bromo-2-methyl-6-quinolinol (30.1 g, 126 mmol),(R)-benzyl glycidyl ether (24.9 g, 152 mmol) and triethylamine (17.4 g,172 mmol) in DMA (200 mL) was heated in a 95-98° C. oil bath for 2 days.The solution was cooled and poured into water (300 mL) while stirring.The tan precipitate formed was filtered, washed with water (100 mL) anddried in a vacuum oven to give 37 g (73%) of the title compound as a tansolid. R_(f)=0.35 (EtOAc); ¹H NMR (DMSO) δ 8.31 (d, J=8.8 Hz, 1H), 7.96(d, J=9.2 Hz, 1H), 7.72 (d, J=9.3 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H),7.25-7.36 (m, 5H), 5.28 (d, J=5.1 Hz, 1H), 4.56 (s, 2H), 4.22-4.29 (m,2H), 4.08-4.15 (m, 1H), 3.61-3.73 (m, 2H), 2.66 (s, 3H); Specificrotation=+6.2° (c=1, CH₃OH);

Elemental Analysis for: C₂₀H₂₀BrNO₃ Calc'd: C, 59.66; H, 4.97; N, 3.48Found: C, 59.43; H, 4.97; N, 3.55

Intermediate 21(2S)-2[(Benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline

To a mixture of(2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol(100 g, 0.249 mol) and copper (I) iodide (47.4 g, 0.249 mol) in toluene(2 L), NaH (10.9 g, 0.45 mol) was added in portions at 30-35° C. over 20min. The reaction mixture was kept at 35° C. for 30 min then heated to110° C. slowly. After 30 min, the reaction was cooled to 60° C.,additional NaH (10.9 g, 0.45 mol) was added. This was warmed to 110° C.for an additional 2 hours then cooled to room temperature beforedropwise addition of water (200 mL). After stirring for 15 min, themixture was filtered through a bed of celite then washed with toluene(3×50 mL) and water (50 mL). The two layers were separated. The organiclayer was extracted with water (100 mL), NH₄OH (100 mL), 25% NaCl (100mL) and concentrated in vacuo to give 387.6 g of the crude product as abrown syrup. The crude product was carried through to the debenzylationstep before purification.

Intermediate 22[(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methanol

To a solution of(2S)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline(0.16 g, 0.5 mmol) in EtOH (1 mL) was added cyclohexene (0.5 mL) then10% Pd/C (0.016 g, 10 mol %). The mixture was heated to reflux under N₂for 18 h then cooled and filtered. The catalyst was rinsed with methanoland the filtrate was concentrated in vacuo to afford 0.113 g (98%) ofthe title alcohol as an off-white solid.

¹H NMR (CD₃OD) δ 8.46 (m, 1H), 7.47 (m, 1H), 7.38-7.31 (m, 2H), 4.40 (m,1H), 4.36 (m, 1H), 4.18 (m, 1H), 3.91 (m, 2H), 2.68 (s, 3H).

Intermediate 23[(2R)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methyl4-Bromobenzenesulfonate

A solution of[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol(4.0 g, 17.3 mmol), brosyl chloride (4.86 g, 19.0 mmol), dimethylaminopyridine (20 mg, 0.16 mmol) and triethylamine (3.62 mL, 25.8 mmol) intoluene (40 mL) was stirred at 60° C. for 6 h. The reaction mixture wascooled to room temperature then water (20 mL) was added. After 30 min,the two layers were separated. The organic layer was extracted with 8%NaHCO₃ (20 mL) and H₂O (20 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The solid obtained was dissolved in isopropylalcohol (50 mL) and toluene (10 mL) at 80° C., cooled to roomtemperature over 1 h then filtered, washed with (5:1) IPA: toluene (2×5mL) and dried in a vacuum oven to give 5.99 g (76.9%) of the titlecompound as an off-white solid. ¹³C NMR (CDCl₃) δ 157.9, 144.3, 138.1,134.7, 132.9, 129.7, 129.6, 129.0, 122.4, 121.7, 121.3, 118.8, 70.7,67.6, 64.5, 25.4

Intermediate 24 1-Benzhydryl-azetidin-3-one

Triethylamine (11.6 ml, 42 mmol) was added to a solution of1-benzhydryl-azetidin-3-ol (2.0 g, 4.2 mmol) in dimethylsulfoxide (60mL) at room temperature. The resulting mixture was cooled to 10° C.,then pyridine sulfur trioxide (8.64 g, 33.6 mmol) in dimethylsulfoxidewas introduced. The mixture was stirred at 10° C. for 1 hour and thenfor 2 hours at room temperature. The reaction mixture was poured intowater (100 mL) and extracted with methylene chloride (3×100 mL). Theorganic layer was washed with water (3×150 mL), dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The crude oilwas column chromatographed on silica gel (30% ethyl acetate-hexane). Theproduct-containing fractions were concentrated under vacuum to give 1.7g (86%) of the title compound as a yellow solid, m.p. 52-54° C.

Intermediate 25 1-Benzhydryl-3-methoxymethylene-azetidine

To a suspension of sodium hydride (60% mineral oil dispersion, 0.10 g,2.3 mmol) in anhydrous tetrahydrofuran (30 mL) was added(methyoxymethyl)triphenylphosphonium chloride (0.80 g, 2.3 mmol) at 0°C. The mixture was stirred at 0° C. for 40 minutes, then a solution of1-benzhydryl-azetidin-3-one (0.50 g, 2.1 mmol) in tetrahydrofuran wasintroduced at 0° C. The resulting mixture was refluxed for 2 hours. Thereaction was quenched with water and extracted with methylene chloride(3×50 mL). The organic layer was washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuum. The crudeoil was column chromatographed on silica gel (20% ethyl acetate-hexane).The product-containing fractions were concentrated under vacuum to give0.29 g (52%) of the title compound as a light yellow solid, m.p. 56-58°C.

Elemental Analysis for: C₁₈H₁₉NO Calc'd: C, 81.48; H, 7.22; N, 5.28Found: C, 81.03; H, 7.24; N, 5.19

Intermediate 26 (1-Benzhydryl-azetidin-3-yl)-acetaldehyde

A solution of 1-benzhydryl-3-methoxymethylene-azetidine (0.19 g, 0.88mmol) in tetrahydrofuran (20 mL) and 1N hydrogen chloride (10 mL) wasrefluxed overnight. The mixture was neutralized with saturated sodiumbicarbonate and extracted with methylene chloride (3×50 mL). Thecombined organic extracts were washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuum to afford0.17 g of the title compound as a light yellow oil.

¹H NMR (400 MHz, DMSO-D₆): δ 3.2 (br, 4H), 4.42 (s, 1H), 7.13-7.18 (m,2H), 7.23-7.27 (m, 4H), 7.37-7.40 (m, 4H).

Intermediate 271-[(1-Benzhydryl-azetidin-3-yl)-methoxy-methyl]-5-fluoro-1H-indole

A solution of (1-benzhydryl-azetidin-3-yl)-acetaldehyde (0.30 g, 1.2mmol), 5-fluoroindole (0.8 g, 6.0 mmol) and sodium hydroxide (0.6 g, 1.6mmol) in methanol (20 mL) was refluxed for 6 hours. The reaction wasquenched with water and extracted with methylene chloride (3×100 mL).The organic layer was washed with water (3×80 mL), dried over anhydroussodium sulfate, filtered and concentrated in vacuum. The crude oil wascolumn chromatographed on silica gel (30-40% ethyl acetate/hexane). Theproduct-containing fractions were concentrated under vacuum to give 0.27g (56%) of the title compound as a light yellow oil. ¹H NMR (500 MHz,DMSO-D₆): δ 2.62 (t, J=6.4 Hz, 1H), 2.90-2.95 (m, 2H), 3.02 (t, J=6.1Hz, 1H), 3.09 (s, 3H), 3.26-3.31 (m, 1H), 4.40 (br, 1H), 4.58 (d, J=8.8Hz, 1H), 6.89 (m, 1H), 7.13-7.18 (m, 2H), 7.22-7.27 (m, 4H), 7.31-7.39(m, 7H) 11.10 (br, 1H).

Intermediate 281-[(1-Benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole

This compound was prepared as described for Intermediate 27, using(1-benzhydryl-azetidin-3-yl)-acetaldehyde (0.3 g, 1.2 mmol) and indole(0.7 g, 6.0 mmol), to afford 0.23 g of the title compound as a clearoil.

¹H NMR (500 MHz, DMSO-D₆): δ 2.62 (t, J=6.7 Hz, 1H), 2.89 (t, J=7.1 Hz,1H), 2.98 (m, 1H), 3.03 (t, J=6.7 Hz, 1H), 3.09 (s, 3H), 3.28 (t, J =7.1Hz, 1H), 4.39 (br, 1H), 4.60 (d, J=8.8 Hz, 1H), 6.97 (m, 1H), 7.04-7.07(m, 1H), 7.12-7.17 (m, 2H), 7.22-7.29 (m, 5H), 7.33 (m, 1H), 7.37-7.41(m, 4H), 7.61 (m, 1H), 10.98 (br, 1H).

Intermediate 293-[(1-Benzhydryl-3-azetidine-3-ylmethyl]-5-fluoro-1H-indole

A solution of1-[(1-benzhydryl-azetidin-3-yl)-methoxy-methyl]-5-fluoro-1H-indole (0.34g, 0.84 mmol), triethylsilane (2.7 mL, 17 mmol) and trifluoroacetic acid(3.2 mL, 42 mmol) in methylene chloride (20 mL) was refluxed overnight.The reaction was poured into ice and neutralized with concentratedammonium hydroxide. The mixture was extracted with methylene chloride(3×100 mL). The combined organic extracts were washed with water (3×80mL), dried over anhydrous sodium sulfate, filtered and concentrated invacuum. The resulting crude oil was column chromatographed on silica gel(40% ethyl acetate/hexane). The product-containing fractions wereconcentrated under vacuum to give 0.32 g (100%) of the title compound asa clear oil. ¹H NMR (500 MHz, DMSO-D₆): δ 2.70-2.78 (m, 3H), 2.88 (d,J=7.1Hz, 2H), 3,.22 (t, J=7.0 Hz, 2H), 4.40 (br, 1H), 6.86-6.90 (m, 1H),7.15-7.18 (m, 3H), 7.22-7.31 (m, 6H), 7.40-7.42 (m, 4H), 10.85 (br, 1H).

Intermediate 30 3-[(1-Benzhydryl-3-azetidine-3-ylmethyl]-1H-indole

This compound was prepared as described for Intermediate 29, using1-[(1-benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole (1.39 g, 3.6mmol), triethylsilane (11.6 ml, 72 mmol) and trifluoroacetic acid (13.7mL, 0.18 mol), to afford 0.66 g of the title compound as a light brownoil. ¹H NMR (500 MHz, DMSO-D₆): δ 2.72-2.79 (m 3H), 2.91 (d, J=7.0 Hz,2H), 3.22 (t, J=6.8 Hz, 2H), 4.39 (br, 1H), 6.95 (m, 1H0, 7.02-7.05 (m,2H0, 7.14-7.17 (m, 2H0, 7.24-7.31 (m, 5H), 7.41-7.42 (m, 4H), 7.48 (m1H), 10.74 (br, 1H).

Intermediate 31 3-Azetidin-3-ylmethyl-5-fluoro-1H-indole

A mixture of 3-[(1-benzhydryl-3-azetidine-3-ylmethyl]-5-fluoro-1H-indole(0.47 g, 1.3 mmol), palladium on carbon (10%, ˜0.1 g) and ammoniumformate (0.16 g, 2.6 mmol) in ethanol (20 mL) was refluxed for 2 hours.The mixture was filtered through celite and the solvent removed undervacuum. Diphenylmethane was removed by triturating the residue withether, methylene chloride and decanting. The remaining product was driedunder vacuum to give 0.19 g of the title compound.

Intermediate 32 3-Azetidin-3-ylmethyl-1H-indole

This compound was prepared as described for Intermediate 31, using3-[(1-benzhydryl-3-azetidine-3-ylmethyl]-1H-indole (0.66 g, 1.9 mmol)palladium on carbon (10%, ˜0.1 g) and ammonium formate (0.35 g, 5.7mmol), to afford 0.22 g of the title compound as a off-white solid, m.p.146-147.5° C. ¹H NMR (500 MHz, DMSO-D₆): δ 2.90-2.95 (m, 3H), 3.25 (t,J=6.7 Hz, 2H), 3.48 (t, J=7.0 Hz, 2H0, 6.96 (m, 1H), 7.04-7.07 (m, 2H),7.32 (d, J=8.1 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H0, 10.75 (br, 1H).

Intermediate 333-(1-Benzhydryl-azetidin-3-ylmethyl)-5-fluoro-1-methyl-1H-indole

To a suspension of sodium hydride (60% mineral oil dispersion, 0.04 g,1.0 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added3-azetidin-3-ylmethyl-5-fluoro-1H-indole in DMF at −10° C. The resultingmixture was stirred for 20 min at −10° C., then methyl iodide (0.06 mL,1.0 mmol) was introduced. The mixture was stirred for another 0.5 hourat −10° C. and then quenched with water. The mixture was extracted withmethylene chloride (3×100 mL). The organic layer was washed with water(3×80 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuum. The crude oil was column chromatographed onsilica gel (20% ethyl acetate-hexane/hexane). The product-containingfractions were concentrated under vacuum to give 0.32 g of the titlecompound as a clear oil. ¹H NMR (500 MHz, DMSO-D₆): δ 2.62-2.73 (m, 3H),2.82 (d, J=7.4 Hz, 2H), 3.18 (t, J=7.0 Hz, 2H), 3.27 (s, 3H), 4.35 (br,1H), 6.87-6.92 (m, 1H), 7.07-7.13 (m, 3H), 7.130-7.23 (m, 5H), 7.28-7.31(m, 1H), 7.35-7.37 (m, 4H).

Intermediate 34 3-Azetidin-3-ylmethyl-5-fluoro-1-methyl-1H-indole

This compound was prepared as described for Intermediate 31, using3-(1-benzhydryl-azetidin-3-ylmethyl)-5-fluoro-1-methyl-1H-indole (0.37g, 0.94 mmol), palladium on carbon (10%, ˜0.1 g) and ammonium formate(0.24 g, 2.8 mmol), to afford 0.18 g of the title compound as a clearoil. The oxalate was prepared in ethanol and collected as a white solid,m.p. 155-156° C.

Elemental Analysis for: C₁₃15₄FN₂.C₂H₂O₄ Calc'd: C, 58.38; H, 5.55; N,9.08 Found: C, 58.44; H, 5.45; N, 9.04

EXAMPLE 12-[3-(5-Fluoro-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

A solution of (2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.35g,.0.80 mmol), 3-azetidin-3-ylmethyl-5-fluoro-1H-indole (0.19 g, 0.96mmol) and triethylamine (0.16 mL, 1.2 mmol) in dimethylsulfoxide (20 mL)was heated at 90° C. under nitrogen overnight. The reaction mixture wasquenched with 1N sodium hydroxide and extracted with methylene chloride(3×80 mL). The organic layer was washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered, and concentrated in vacuum. Theresulting crude oil was column chromatographed on silica gel (3%methanol-ethyl acetate). The product-containing fractions wereconcentrated in vacuum to give 0.090 g of the (S)-enantiomer of thetitle compound as a brown oil. The dihydrochloride salt was prepared inethyl acetate and collected as 0.068 g of a yellow solid, m.p. 125° C.(dec).

Elemental Analysis for: C₂₅H₂₄FN₃O₂.2HCl.3H₂O Calc'd: C, 55.15; H, 5.92;N, 7.72 Found: C, 55.20; H, 5.73; N, 7.68

EXAMPLE 22-[3-(5-Fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

A solution of (2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.090g, 0.24 mmol), 5-fluoro-3-piperidin-3-ylmethyl-1H-indole (0.56 g, 0.24mmol) and triethylamine (0.042 mL, 0.36 mmol) in dimethylsulfoxide (10mL) was heated at 90° C. under nitrogen overnight. The reaction mixturewas quenched with 1N sodium hydroxide and extracted with methylenechloride (3×50 mL). The organic layer was washed with water (3×50 mL),dried over anhydrous sodium sulfate, filtered, and concentrated invacuum. The crude oil was column chromatographed on silica gel (5%methanol-75% ethyl acetate-20% hexane). The product-containing fractionswere concentrated in vacuum to give 0.048 g (53%) of the (S)-enantiomerof the title compound as a brown oil. The dihydrochloride salt wasprepared in ethyl acetate and collected as 0.037 g of a yellow solid,m.p. 68° C. (dec).

Elemental Analysis for: C₂₇H₂₈FN₃O₂.2HCl.2H₂O.0.5EtOAc Calc'd: C, 58.19;H, 6.40; N, 7.02 Found: C, 58.12; H, 6.28; N, 6.90

EXAMPLE 32-[3-(6-Fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

This compound was prepared as described for Example 2, using(2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.22g, 4.9 mmol), 6-fluoro-3-piperidin-3-ylmethyl-1H-indole (0.13 g, 5.9mmol), to afford 0.11 g (50%) of the (S)-enantiomer of the titlecompound as a light brown oil. The hydrogen chloride salt was preparedin ethyl acetate and collected as 0.12 g of a yellow solid, m.p. 50° C.(dec).

Elemental Analysis for: C₂₇H₂₈FN₃O₂.2HCl.3.5H₂O Calc'd: C, 55.77; H,6.41; N, 7.23 Found: C, 55.46; H, 6.21; N, 6.89

EXAMPLE 42-[3-(1H-Indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

This compound was prepared as described for Example 1, using(2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.26g, 0.59 mmol), 3-azetidin-3-ylmethyl-1H-indole (0.11 g, 0.59 mmol), toafford 0.035 g of the (S)-enantiomer of the title compound as a lightbrown foam. ¹H NMR (500 MHz, DMSO-D₆): δ 2.74-2.82 (m, 3H), 2.90 (d,J=7.5 Hz, 2H), 2.96 (t, J=6.6 Hz, 2H), 3.03 (t, J=6.6 Hz, 2H), 3.51 (t,J=6.8 Hz, 2H), 3.42 (t, J=6.8 Hz, 2H), 4.08 (m, 1H), 4.30-4.32 (m, 1H),4.37 (m, 1H), 6.94-6.97 (m, 1H), 7.04-7.08 (m, 2H), 7.30-7.36 (m, 3H),7.42 (d, J=9.1Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H).

EXAMPLE 52-[3-(5-Fluoro-1-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

This compound was prepared as described for Example 2, using(2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.24g, 0.53 mmol), 3-azetidin-3-ylmethyl-5-fluoro-1-methyl-1H-indole (0.12g, 0.53 mmol), to afford 0.65 g of the (S)-enantiomer of the titlecompound as a light brown oil. The oxalate was prepared in methanol andcollected as 0.047 g of a yellow solid, m.p. 193-195° C.

Elemental Analysis for: C₂₆H₂₆FN₃O₂.2C₂H₂O₄.1.25H₂O Calc'd: C, 56.83; H,5.17; N, 6.63 Found: C, 56.56; H, 4.76; N, 6.52

Intermediate 35 6-Fluoro-1-piperidin-4-ylmethyl-1H-indole

To 6-fluoroindole (1.35 g, 10.0 mmol) in N,N-dimethylformamide (100 mL)was added a 60% mineral oil dispersion of sodium hydride (0.44 g, 11mmol). The mixture was stirred at room temperature under nitrogen for 30min, then 4-tosyloxymethyl-N-carbobenzyloxypiperidine (4.0 g, 10 mmol)added and the mixture heated at 70° C. under nitrogen for 16 hours. Thesolvent was removed in vacuum and replaced with methylene chloride (350mL). The solution was washed with 250 mL portions of 2N aqueoushydrochloric acid, saturated aqueous sodium bicarbonate and saturatedbrine and dried over sodium sulfate. Filtration, concentration in vacuumand column chromatography on silica gel with methylene chloride aseluent gave 3.7 g of4-(6-fluoro-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl ester.This material was dissolved in ethyl acetate (100 mL), 10% Pd on carbon(0.50 g) and cyclohexene (3.2 g, 40 mmol) added, and the mixturerefluxed under nitrogen for 2 hours. Filtration through celite, followedby concentration in vacuum gave 2.1 g of the title compound as a whitesolid. ¹H-NMR (CDCl₃) doublet of doublets 7.5 δ (1 H); doublet 7.0 δ (1H); doublet of doublets 6.95 δ (1 H); triplet of doublets 6.82 δ (1 H);doublet 6.42 δ (1 H); doublet 3.9 δ (2 H); doublet 3.02 δ (1 H); triplet2.5 δ (2 H); doublet 1.5 δ (2 H); multiplet 1.2 δ (2 H).

EXAMPLE 62-({4-[(6-Fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline

[(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl4-bromobenzene sulfonate (0.90 g, 2.0 mmol) and6-fluoro-1-piperidin-4-ylmethyl-1H-indole (0.70 g, 3.0 mmol) werecombined in DMSO (10 mL) and heated at 80° C. under nitrogen for 6hours. The mixture was diluted with ethyl acetate (400 mL) and washedwith 300 mL portions of saturated aqueous sodium bicarbonate, water, andsaturated brine, dried over sodium sulfate, filtered and concentrated invacuum to a yellow gum. Column chromatography on silica gel with 1%methanol/chloroform and recrystallization from ethanol with addition offumaric acid gave 0.41 g of the fumarate of the (S)-enantiomer of thetitle compound as a white solid, m.p. 140-142° C.

Elemental Analysis for: C₂₇H₂₈FN₃O₂.C₄H₄O₄.1.5H₂O Calc'd: C, 63.26; H,5.99; N, 7.14 Found: C, 63.58; H, 5.84; N, 7.17

EXAMPLE 72-({4-[(6-Fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline

[(2R)-8-Ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl4-methylbenzene sulfonate (0.50 g, 1.2 mmol) and6-fluoro-1-piperidin-4-ylmethyl-1H-indole (0.70 g, 3.0 mmol) werecombined in DMSO (10 mL) and heated at 80° C. under nitrogen for 6hours. The mixture was diluted with ethyl acetate (400 mL) and washedwith 300 mL portions of saturated aqueous sodium bicarbonate, water, andsaturated brine, dried over sodium sulfate, filtered and concentrated invacuum to a yellow gum. Column chromatography on silica gel with 1%methanol/chloroform and recrystallization from isopropanol with additionof excess HCl gave 0.16 g of the dihydrochloride of the (S)-enantiomerof the title compound as a gold solid, m.p. >250° C.

Elemental Analysis for: C₂₈H₃₀FN₃O₂.2HCl.1.5H₂O Calc'd: C, 60.11; H,6.31; N, 7.51 Found: C, 60.45; H, 6.38; N, 7.15

Intermediate 36 1-Piperidin-4-ylmethyl-1H-indole-6-carbonitrile

To 6-cyanoindole (1.7 g, 12 mmol) in N,N-dimethylformamide (100 mL) wasadded a 60% mineral oil dispersion of sodium hydride (0.48 g, 12 mmol).The mixture was stirred at room temperature under nitrogen for 30 min,then 4-tosyloxymethyl-N-carbobenzyloxypiperidine (4.8 g, 12 mmol) addedand the mixture heated at 80° C. under nitrogen for 15 hours. Thesolvent was removed in vacuum and replaced with methylene chloride (400mL). The solution was washed with 350 mL portions of water, saturatedaqueous sodium bicarbonate, and saturated brine and dried over sodiumsulfate. Filtration, concentration in vacuum and column chromatographyon silica gel with methylene chloride as eluent gave 4.4 g of4-(6-cyano-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl ester.This material was dissolved in ethyl acetate (100 mL), 10% Pd on carbon(0.50 g) and cyclohexene (3.2 g, 40 mmol) added, and the mixturerefluxed under nitrogen for 15 hours. Filtration through celite,followed by concentration in vacuum gave 1.9 g of the title compound asa white solid. ¹H-NMR (CDCl₃): doublet 7.6 δ (1 H); singlet 7.55 δ (1H); doublet 7.2 δ (1 H); singlet 7.13 δ (1 H); singlet 6.25 δ (1 H);doublet 3.9 δ (2 H); doublet 3.02 δ (1 H); triplet 2.45 δ (2 H); doublet1.45 δ (2 H); multiplet 1.18 δ (2 H).

EXAMPLE 81-[(1-{[8-Methyl-2,3-dihydro[1,4]-dioxino[2,3-f]quinolin-2-yl]methyl)piperidin-4-yl]-1H-indole-6-carbonitrile

[(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl4-bromobenzene sulfonate (0.90 g, 2.0 mmol) and1-piperidin-4-ylmethyl-1H-indole-6-carbonitrile (0.72 g, 3.0 mmol) werecombined in DMSO (10 mL) and heated at 80° C. under nitrogen for 6hours. The mixture was diluted with ethyl acetate (400 mL) and washedwith 300 mL portions of saturated aqueous sodium bicarbonate, water, andsaturated brine, dried over sodium sulfate, filtered and concentrated invacuum to a yellow gum. Column chromatography on silica gel with 1%methanol/chloroform and recrystallization from ethanol with addition offumaric acid gave 0.40 g of the fumarate of the (S)-enantiomer of thetitle compound as a white solid, m.p. 178-180° C.

Elemental Analysis for: C₂₈H₂₈N₄O₂.C₄H₄O₄.0.65H₂O Calc'd: C, 66.23; H,5.78; N, 9.65 Found: C, 65.89; H, 5.66; N, 9.91

Intermediate 37 1-(1-Benzhydryl-azetidin-3-ylmethyl)-6-fluoro-1H-indole

To a suspension of sodium hydride (60% mineral oil dispersion, 0.19 g,4.6 mmol) in anhydrous DMF (20 mL) was added 6-fluoroindole (0.65. g,2.6 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, thena solution of methanesulfonic acid 1-benzhydryl-azetidine-3-ylmethylester (0.78 g, 2.3 mmol) in DMF was introduced at 0° C. The resultingmixture heated at 60° C. for 16 hours. The reaction was quenched withwater and extracted with methylene chloride (3×50 mL). The organic layerwas washed with water (3×50 mL), dried over anhydrous sodium sulfate,filtered and the solvent removed under vacuum. The crude oil was columnchromatographed on silica gel (10-30% ethyl acetate-hexane). Theproduct-containing fractions were concentrated under vacuum to give 0.60g (52%) of the title compound as a light brown oil. MS ES m/e 371(M+H)⁺; ¹H NMR (500 MHz, DMSO-D₆): 2.76-2.79 δ (m, 3H), 3.05-3.07 δ (m,2H), 4.29-4.31 δ (m, 3H), 6.37 δ (m, 1H), 6.78-6.83 δ (m, 1H), 7.09-7.13δ (m, 2H), 7.18-7.22 δ (m, 4H), 7.31-7.35 δ (m, 6H), 7.46 δ (m, 1H).

Intermediate 38 1-Azetidin-3-ylmethyl-6-fluoro-1H-indole

A mixture of 1-(1-benzhydryl-azetidin-3-ylmethyl)-6-fluoro-1H-indole(0.6 g, 1.6 mmol), palladium on carbon (10%, cat.amount) and ammoniumformate (0.2 g, 3.2 mmol) in ethanol (20 mL) was refluxed for 30 min.The mixture was filtered through celite and the solvent removed undervacuum. Diphenylmethane was removed by triturating the residue withether, methylene chloride and decanting. The remaining product was driedunder vacuum. The crude material was directly used in next step withoutfurther purification.

EXAMPLE 92-[3-(6-Fluoro-indol-1-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

A solution of (2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.4g, 0.93 mmol), 1-azetidin-3-ylmethyl-6-fluoro-1H-indole (0.19 g, 0.93mmol) and triethylamine (0.19 ml, 1.4 mmol) in dimethylsulfoxide (20 ml)was heated at 90° C. under nitrogen overnight. The reaction mixture wasquenched with 1N sodium hydroxide and extracted with methylene chloride(3×80 mL). The organic layer was washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered and the solvent removed under vacuum.The crude oil was column chromatographed on silica gel (3%methanol-ethyl acetate). The product-containing fractions wereconcentrated in vacuum to give 0.1 g of the (S)-enantiomer of the titlecompound as a brown oil. The hydrogen chloride salt was prepared inethyl acetate and collected as a yellow solid: mp: 138° C. (dec).

Elemental Analysis for: C₂₅H₂₄FN₃O₂.2HCl.2.25 H₂O Calc'd: C, 56.56; H,5.79; N, 7.91 Found: C, 56.59; H, 5.87; N, 7.83

Intermediate 393-[2-(6-Fluoro-indol-1-yl)-ethyl]ethyl]-azetidine-1-carboxylic acidtert-butyl ester

To a suspension of sodium hydride (60% mineral oil dispersion, 0.42 g,10.5 mmol) in anhydrous DMF (40 mL) was added 6-fluoroindole (1.28 g,5.0 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, thena solution of 3-[2 (toluene-4-sulfonyloxy)-ethyl]-azetidine-1-carboxylicacid tert-butyl ester (1.51 g, 4.2 mmol) in DMF was introduced at 0° C.The resulting mixture heated at 60° C. overnight. The reaction wasquenched with water and extracted with methylene chloride (3×50 mL). Theorganic layer was washed with water (3×50 mL), dried over anhydroussodium sulfate, filtered and solvent removed under vacuum. The crude oilwas column chromatographed on silica gel (20% ethyl acetate-hexane). Theproduct-containing fractions were concentrated under vacuum to give 0.89g (66%) of the title compound as a light brown oil. MS ES m/e 637(2M+H)⁺; ¹H NMR (500 MHz, DMSO-D₆): 1.29 δ (s, 9H), 1.92-1.97 δ (m, 2H),2.33 δ (m, 1H), 3.3 δ (br, 2H), 3.73 δ (br, 2H), 4.08 δ (t, J=6.9 Hz,2H), 6.39-6.40 δ (m, 1H), 6.82 δ (m, 1H), 7.32 δ (m, 2H), 7.48 δ (dd,J=5.5, 8.7 Hz, 1H).

Intermediate 40 1-(2-Azetidin-3-yl-ethyl)-6-fluoro-1H-indole (4)

A solution of3-[2-(6-fluoro-indol-1-yl)-ethyl]ethyl]-azetidine-1-carboxylic acidtert-butyl ester (43 mg, 0.14 mmol) and ethereal hydrochloric acid (0.27mL, 0.26 mmol) in methanol (10 mL) was refluxed for 2 hours. The solventwas removed under vacuum and the crude oil was washed with saturatedsodium bicarbonate. The mixture was extracted with methylene chloride(3×80 mL). The organic layer was washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered and the solvent removed under vacuumto give 29 mg of product as a brown oil. The hydrogen chloride salt wasprepared using excess ethereal hydrochloric acid to yield 20 mg of thetitle compound as a yellow solid hydrochloride, m.p. 120-123° C.

Elemental Analysis for: C₁₃H₁₅FN₂.HCl.0.4H₂O Calc'd: C, 59.61; H, 6.46;N, 10.69 Found: C, 59.67; H, 6.36; N, 10.59

EXAMPLE 102-{3-[2-(6-Fluoro-indol-1-yl)-ethyl]-azetidin-1-ylmethyl}-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

A solution of (2R)-4-bromobenzenesulfonic acid8-methyl-2,3dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.43g, 0.79 mmol) 1-(2-azetidin-3-yl-ethyl)-6-fluoro-1H-indole (0.25 g, 0.95mmol) and triethylamine (0.2 mL, 1.4 mmol) in dimethylsulfoxide (20 mL)was heated at 90° C. under nitrogen overnight. The reaction mixture wasquenched with 1N sodium hydroxide and extracted with methylene chloride(3×80 mL). The organic layer was washed with water (3×50 mL), dried overanhydrous sodium sulfate, filtered and the solvent removed under vacuum.The crude oil was column chromatographed on silica gel (10%methanol-ethyl acetate). The product-containing fractions wereconcentrated in vacuum to give 0.3 g of the (S)-enantiomer of the titlecompound as a brown oil. The hydrochloride salt was prepared in ethylacetate and collected as a yellow solid: m.p. 115° C. (dec).

Elemental Analysis for: C₂₆H₂₆FN₃O₂.2HCl.2H₂O Calc'd: C, 57.78; H, 5.97;N, 7.77 Found: C, 57.48; H, 5.92; N, 7.60

EXAMPLE 111-{2-[1-(8-Methyl-2,3-dihydro-[1,4]-dioxino[2,3-f]quinolin-2-ylmethyl)-azetidin-3-yl]-ethyl}-1H-indole-6-carbonitrile

A solution of (2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.21g, 0.45 mmol) 1-(2-azetidin-3-yl-ethyl)-1H-indole-6-carbonitrile (0.11g, 0.52 mmol), which was made in two steps from 6-cyanoindole accordingto the procedures described for Intermediates 40 and 41, andtriethylamine (0.14 ml, 1 mmol) in dimethylsulfoxide (20 ml) was heatedat 90° C. under nitrogen overnight. The reaction mixture was quenchedwith 1N sodium hydroxide and extracted with methylene chloride (3×80ml). The organic layer was washed with water (3×50 ml), dried overanhydrous sodium sulfate, filtered and the solvent removed under vacuum.The crude oil was column chromatographed on silica gel (10%methanol-ethyl acetate). The product-containing fractions wereconcentrated in vacuum to give 0.08 g of the (S)-enantiomer of the titlecompound as a brown oil. The hydrochloride salt was prepared in ethylacetate and collected as a yellow solid: yellow solid, m.p. 144° C.(dec).

Elemental Analysis for: C₂₇H₂₆FN₄O₂.2HCl.2.5H₂O Calc'd: C, 58.28; H,5.98; N, 10.07 Found: C, 58.27; H, 5.69; N, 10.00

Intermediate 413-[(1-Benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole-5-carbonitrile

A solution of 1-benzhydryl-3-azetidine-3-carbaldehyde (1.0 g, 4.0 mmol),5-cyanoindole (2.8 g, 20 mmol), and sodium hydroxide (0.19 g, 4.8 mmol)in methanol (40 ml) was refluxed for 6 hours. The reaction was quenchedwith water and extracted with methylene chloride (3×100 ml). The organiclayer was washed with water (3×80 ml), dried over anhydrous sodiumsulfate, filtered and solvent removed under vacuum. The crude oil waschromatographed on Biotage (30-40% ethyl acetate-hexane/hexane). Theproduct-containing fractions were concentrated under vacuum to give 0.7g (43%) of the title compound as a light yellow oil. MS ES m/e 406(M−H)⁻; ¹H NMR (500 MHz, DMSO-D₆): 2.42 δ (m, 1H), 2.58 δ (m, 1H), 2.85δ (m, 1H), 2.91-2.99 δ (m, 2H), 3.05 δ (s, 3H), 4.35 δ (br, 1H), 4.62 δ(d, J=8.8 Hz, 1H), 7.07-7.21 δ (m, 5H), 7.23-7.38 δ (m, 6H), 7.47 δ (m,2H), 8.07 δ (m, 1H), 11.54 δ (br, 1H).

Intermediate 423-(1-Benzhydryl-azetidin-3-ylmethyl)-1H-indole-5-carbonitrile

A solution of3-[(1-benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole-5-carbonitrile,triethylsilane (5.5 ml, 34 mmol) and trifluoroacetic acid (6.6 mL, 86mmol) in methylene chloride (40 mL) was refluxed overnight. The reactionwas poured into ice and neutralized with concentrated ammoniumhydroxide. The mixture was extracted with methylene chloride (3×100 mL).The organic layer was washed with water (3×80 mL), dried over anhydroussodium sulfate, filtered and solvent removed under vacuum. The crude oilwas column chromatographed on a Biotage (40% ethylacetate-hexane/hexane). The product-containing fractions wereconcentrated under vacuum to give 0.56 g (86%) of the title compound asa clear oil. MS ES m/e 378 (M+H)⁺; ¹H NMR (500 MHz, DMSO-D₆): 2.74-2.78δ (M, 3H), 2.96 δ (d J=6.7 Hz, 2H), 3.21 δ (t, J=6.4 Hz, 2H), 4.4 δ (s,1H), 7.15-7.17 δ (m, 2H), 7.24-7.29 δ (m, 5H), 7.38-7.418 δ (m, 5H),7.47 δ (d, J=8.4 Hz, 1H), 8.07 δ (s, 1H), 11.37 δ (br, 1H).

Intermediate 43 3-Azetidin-3-ylmethyl-5-methyl-1H-indole

A mixture of3-(1-benzhydryl-azetidin-3-ylmethyl)-1H-indole-5-carbonitrile (8) (0.56g, 1.5 mmol), palladium on carbon (10%, 0.1 g) and ammonium formate(0.37 g, 5.9 mmol) in ethanol (20 ml) was refluxed for 2 hours. Themixture was filtered through celite and the solvent removed undervacuum. Diphenylmethane was removed by triturating the residue withether, methylene chloride and decanting. The remaining product was driedunder vacuum. The crude material was directly used in next step. MS ESm/e 200 (M+H)⁺.

EXAMPLE 128-Methyl-2-[3-(5-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

This compound was prepared as described for Example 10, using(2R)-4-bromobenzenesulfonic acid8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.4g, 0.9 mmol), 3-azetidin-3-ylmethyl-5-methyl-1H-indole (0.19 g, 0.9mmol), to afford 0.15 g of the (S)-enantiomer of the title compound as alight brown oil. The hydrochloride salt was prepared in ethyl acetateand collected as a yellow solid, m.p. 150° C. (dec).

Elemental Analysis for: C₂₆H₂₄N₄O₂.2HCl.2.5H₂O Calc'd: C, 58.76; H,6.45; N, 7.95 Found: C, 58.82; H, 6.23; N, 7.77

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges specific embodiments thereinare intended to be included.

The disclosures of each patent, patent application, and publicationcited or described in this document are herby incorporated herein byreference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A method of treating a subject suffering from a condition selectedfrom depression, anxiety, panic disorder, post-traumatic stressdisorder, premenstrual dysphoric disorder, attention deficit disorder,obsessive compulsive disorder, social anxiety disorder, generalizedanxiety disorder, obesity, eating disorders, vasomotor flushing, cocaineand alcohol addiction, and sexual dysfunction, comprising the step of:administering to said subject suffering from said condition atherapeutically effective amount of a compound selected from the groupconsisting of:2-[3-(5-fluoro-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;2-[3-(5-fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;2-[3-(6-fluoro-1H-indol-3-ylmethyl)-piperidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;2-[3-(1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;2-[3-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;2-({4-[(6-fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;2-({4-[(6-fluoro-1H-indol-1-yl)methyl]piperidin-1-yl}-8-ethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;1-[(1-{[8-methyl-2,3-dihydro[1,4]-dioxino[2,3-f]quinolin-2-yl]methyl)piperidin-4-yl]-1H-indole-6-carbonitrile;2-[3-(6-fluoro-indol-1-ylmethyl)-azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;2-{3-[2-(6-fluoro-indol-1-yl)-ethyl]-azetidin-1-ylmethyl}-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;1-{2-[1-(8-methyl-2,3-dihydro-[1,4]-dioxino[2,3-f]quinolin-2-ylmethyl)-azetinin-3-yl]-ethyl}-1H-indole-6-carbonitrile;and 8-methyl-2-[3-(5-methyl-1H-indol-3-ylmethyl)-azetidin-1-ylmethyl]-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline; or apharmaceutically acceptable salt thereof.
 2. A method according to claim1, wherein the condition is depression.
 3. A method according to claim1, wherein the condition is selected from the group consisting ofobsessive-compulsive disorder, panic attacks, generalized anxietydisorder, and social anxiety disorder.
 4. A method according to claim 1,wherein said compound is the S enantiomer at the2-aminomethyl-2,3-dihydro-1,4-benzodioxan moiety, substantially free ofthe R enantiomer of said compound.